Traumatic brain injury (TBI) is common in adolescents and young adults and is frequently associated with a high risk for long-term disability and mortality. Unique to pediatric TBI is the increased danger of developing cerebral edema, a phenomenon thought to be related to higher brain water content in the young and to developmental differences of the brain's response to injury. Likewise, the developing brain is more susceptible to excitotoxic, apoptotic and inflammatory injury at a time when plasticity is critical in promoting endogenous recovery as well as in response to exogenous pharmaceutical treatment. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPs;c-Jun N terminal kinase, c-JNK) play critical roles at different overlapping points in the cascade of events after ischemic and traumatic brain injury. AQPs are a unique class of water channels and AQP4, the most abundant brain AQP, plays a critical role in edema formation and constitutes an excellent molecular candidate for the development of novel agents to reduce post-TBI edema. AQPs also recently have been shown to participate in other pathways that contribute to brain injury and repair. JNK pathways, mediated by glutamate-calcium activation, trigger mitochondrial cascades of programmed cell death, accelerate MAP kinase neuronal death and participate in production of proinflammatory mediators from glial cells. Of great clinical interest is that in the last two years novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4;and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents can inhibit these two proteins/pathways and that when combined they will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile TBI model. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is common in children and adolescents and is frequently associated with a high risk of long-term disability and mortality. Unique to pediatric TBI is the greater danger of developing cerebral edema, as well as the greater susceptibility to excitotoxic, apoptotic and inflammatory injury. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPS;c-Jun N terminal kinase, c-JNK) play critical roles in the cascade of events after ischemia and TBI. Novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4;and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents will inhibit these two proteins/pathways and this will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile controlled cortical impact model of TBI.